Molecular Targets of Naturopathy in Cancer Research

14 Pages·2015·0.19 MB·English

Nutrients 2015, 7, 321-334; doi:10.3390/nu7010321
OPEN ACCESS
nutrients
ISSN 2072-6643
www.mdpi.com/journal/nutrients
Review
Molecular Targets of Naturopathy in Cancer Research:
Bridge to Modern Medicine
Aamir Ahmad 1, Kevin R. Ginnebaugh 1, Yiwei Li 1, Subhash B. Padhye 2 and
Fazlul H. Sarkar 1,3,*
1 Department of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University
School of Medicine, Detroit, MI 48201, USA; E-Mails: [email protected] (A.A.);
[email protected] (K.R.G.); [email protected] (Y.L.)
2 Interdisciplinary Science & Technology Research Academy Department of Chemistry, Maharashtra
Cosmopolitan Education Society’s Abeda Inamdar Senior College of Arts, Science and Commerce,
Pune 411001, India; E-Mail: [email protected]
3 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine,
Detroit, MI 48201, USA
* Author to whom correspondence should be addressed; E-Mail: [email protected];
Tel.: [phone]; Fax: [phone].
Received: 13 November 2014 / Accepted: 23 December 2014 / Published: 6 January 2015

Abstract: The relevance of naturopathy (defined as the practice of medicine for the
treatment of human diseases with natural agents) in human cancer is beginning to be
appreciated, as documented by renewed interest in nutraceutical research, the natural
anticancer agents of dietary origin. Because of their pleiotropic effects and the ability to
modulate multiple signaling pathways, which is a good attribute of natural agents,
nutraceuticals have frequently been demonstrated to re-sensitize drug-resistant cancers. The
effectiveness of nutraceuticals can be further enhanced if the tools for the relative assessment
of their molecular targets are readily available. Such information can be critical for
determining their most effective uses. Here, we discuss the anticancer potential of
nutraceuticals and the associated challenges that have interfered with their translational
potential as a naturopathic approach for the management of cancers. In the years to come,
an efficient screening and assessment of molecular targets will be the key to make rapid
progress in the area of drug design and discovery, especially focusing on evidence-based
development of naturopathy for the treatment of human malignancies.
Nutrients 2015, 7 322

Keywords: cancer; naturopathy; nutraceuticals

1. Introduction
Cancer is a difficult disease to manage and treat. For the year 2014, it was projected that a total
of 1,665,540 new cancer cases will be diagnosed in the United States and approximately
585,720 cancer-related deaths will occur [1]. Although these numbers are frightening, it is interesting to
note that the cancer-related mortality has actually declined steadily over last two decades, from
215.1 deaths per 100,000 population in 1991 to 171.8 in 2010 [1]. More than 1.5 million new cases and
more than half a million deaths are big numbers that call for sustained efforts in the fight against cancer.
The decline in cancer deaths is largely due to the more aggressive screenings and early diagnosis of
cancers; but it should not be “mis”-interpreted as evidence of our ability to understand or treat cancer
very effectively.
Human cancers represent a large subset of organ-specific subtypes that are often too unique,
histologically, as well as genomically. One of the biggest challenges in the effective clinical management
of human cancers is the absence of validated therapeutic target(s), especially when evaluating the activity
of natural agents (nutraceuticals). This, in turn, has led to a delay in the development of effective targeted
therapies. In our fight against cancer, it is imperative to find novel treatment options. Traditionally, the
“search” for new treatments has focused on single-targeted agents. Such an approach is based on the
reports on the aberrant expression or mutation of a molecular target, implying that the modulation of
such a target through a targeted therapy can help to control the growth of tumor, while the fundamentals
of cancer biology are typically forgotten, such as that cancer is a heterogeneous disease and the tumor
mass contains a heterogeneous population of cancer cells. However, in recent years, it has been realized
that such a “single”-targeted therapy might not be the most effective approach. The basis for such a
realization is the growing evidence suggesting the switching of cancer cells to alternate survival
pathways when confronted with the inhibition of their primary pathway in addition to the presence of a
heterogeneous population of cancer cells in a tumor mass. Therefore, a multi-targeted therapy comes
across as the most intelligent way of tackling human cancers [2] after many years of denial that
multi-targeting would be the rational approach for killing a heterogeneous population of cancer cells in
a tumor. As its name suggests, this approach calls for a simultaneous targeting of multiple molecular
targets. This can either be accomplished by a combination of a few single-targeted agents or through the
use of a single multi-targeting/pleotropic agent (for example, multi-targeting kinase inhibitors). The
combination of single-targeted agents often results in increased toxicity [3]. It thus emerges that
pleiotropic agents, such as those that occur naturally (by virtue of being natural agents, these agents are
largely non-toxic to humans) and that are part of the normal diets in various cultures, the
“nutraceuticals”, are promising agents for the treatment of cancer [4,5]. Such an approach defines the
importance of “naturopathy” (defined as the practice of medicine for the treatment of human diseases)
as a newer field in cancer research and drug development, especially since this field has been ignored
for many years. In this article, we will discuss the emerging relevance of naturopathy, the various known
molecular targets of nutraceuticals and the assessment of novel targets for naturopathy.
Nutrients 2015, 7 323

2. Naturopathy and Nutraceuticals
Nutraceuticals, or naturally occurring anticancer agents, are pleiotropic in their mode of action [6–16].
As discussed above, cancer is a complex disease that is often a manifestation of multiple deregulated
pathways where cancer cell heterogeneity is the main cause of treatment failure in modern medicine.
Therefore, with their ability to regulate multiple molecular targets, nutraceuticals in a naturopathic
approach stand out as ideal candidates for inhibiting tumorigenesis and/or for achieving better treatment
outcome in patients diagnosed with cancers. The single-targeted agents often fail in clinical trials [17].
Even when they show promise in clinical trials and get approved for use in the clinic, their sustained use
leads to the development of resistance, for which there is no curative treatment. Such drug-resistant
cancers are much more aggressive and difficult to manage and remain one of the leading causes of
cancer-associated morbidity and mortality.
An efficient multi-targeted therapy can be as simple as combining inhibitors of closely-related
pathways, like, for example, kinase inhibitors [18]. It can be envisioned that cancer cells switch their
dependency on closely-related signaling in the case of the suppression of their primary signaling pathway,
collectively known as redundant cell signaling pathways. Such switching to closely-related alternates is
easily accomplished, as opposed to a signaling pathway that is very distinctly related. Thus, simultaneous
inhibition of closely-related signaling pathways is often the first line of research investigation. However,
the use of single-targeted agents has also revealed some more complex scenarios. For example, aromatase
inhibitors are the primary therapy for breast cancer with overexpression of estrogen receptors (ERs) [19],
but it has been reported that resistance to aromatase inhibitors can involve the activation of a very distinct
signaling, the one mediated by HER2 [20]. It is interesting to note that signaling through ERs and HER2
(the tyrosine kinase receptor belonging to the epidermal growth factor receptor family) represents two
major subtypes of breast cancer. This report [20] reveals that suppression of one prominent breast cancer
signaling is overcome by tumor cells by activating an alternate prominent signaling. It was also reported
that HER2 is a negative regulator of ER, and therefore, when HER2 signaling was blocked via targeted
antibody, ER expression goes up, and the aromatase inhibitors could once again become effective.
The study of the mechanism of aromatase inhibitor resistance discussed above [20] teaches us a few
fundamental lessons. First, the inhibition of one major cellular signaling can result in the activation of
an alternate major signaling. Second, there is an immense regulation of cellular signaling in physiological
systems where signaling pathways mutually regulate each other through an overwhelming cross-talk.
HER2 negatively regulates ER, and that is why the authors noted the re-expression of ER when
HER2 was blocked. There is strong evidence of extensive crosstalk between ER and HER2 signaling
pathways [21], which means that the ER, in turn, can negatively regulate HER2. Collectively, this seems
to imply that suppression of ER in ER-dependent tumors can lead to drug-resistance through activation or
de-repression of HER2 signaling, while, on the contrary, suppression of HER2 in HER2 over-expressing
breast cancers can result in resistance to HER2-targeted therapies through activation or de-repression of
ER signaling. This finding, together with many other examples, clearly suggests that a rational approach
for combining multiple agents must be scientifically tested for the treatment of human malignancies.
In order to test whether nutraceuticals can be beneficial in the above scenario because of their
pleiotropic nature, we looked for the reports on the effects of some very well-studied nutraceuticals, such
as curcumin, resveratrol and 3,3′-diiindolylmethane (DIM), on ER and HER2 signaling pathways.
Nutrients 2015, 7 324

Indeed, there is evidence for the modulation of ER signaling [22–26], as well as HER2
signaling [27–30] by curcumin, resveratrol and DIM. These three are not the only nutraceuticals with
anticancer potential, but this quick search did add to the argument that such agents might be beneficial
against ER and HER2 signaling pathways. It should be mentioned that the studies cited here have looked
individually at either ER or the HER2 signaling pathways. Logically, it might make sense to expect an
action of these agents against the two signaling pathways within the same cells, as well.
There is not enough data to either prove or disprove such pleiotropic action of nutraceuticals against
ER and HER2 signaling. However, that is not the main point of discussion. Through the examples of ER
and HER2 signaling, it becomes evident that the suppression of one signaling pathway leads to the
adaptation of cancer cells to an alternate pathway. Considering the growing importance of more signaling
pathways, such as PI3K/Akt, NF-κB, Notch, Wnt, hedgehog, etc., which are relevant to cancer
progression, thus, the cross-talk becomes more extensive. The choice of cancer cells to find an alternate
pathway also increases, and now, it might be argued that targeting of one, two or even more signaling
pathways may still not be the best strategy to suppress tumor growth, while such as a strategy will only
increase unwanted toxicity, which will kill the patients before realizing their treatment benefit. Clearly,
there are so many signaling pathways for the cancer cells to fall back on, and for that reason, a “systems
biology” approach for identifying the most important set of oncogenic pathway is becoming a new era
of modern medicine. Again, pleiotropic agents, such as nutraceuticals, are our best option, because of
their reported activity against virtually every single cancer-relevant signaling pathway [31–37], but most
importantly, for their attributes as non-toxic agents. Therefore, naturopathy would likely become a new
arsenal for combating the fight against cancers.
3. Molecular Targets of Nutraceuticals and Their Cytotoxic Effects
It is quite evident from the discussion above that nutraceuticals are multi-targeting agents. They
modulate an array of signaling pathways, as well as individual molecular targets, and a discussion on
these is beyond the scope of this article. The available literature reveals that natural anticancer agents
have been shown to touch upon virtually every single molecular target. Just to point out a few major
signaling pathways/targets affected by nutraceuticals, we can identify EGFR family receptors, Ras/Raf
signaling, MAPK/ERK pathway, PI3K/Akt/mTOR pathway, Notch family, Wnt/β-catenin signaling,
Sonic hedgehog signaling, hormone receptors (such as ER/progesterone receptor), TGF-β signaling,
insulin-like growth factor signaling, cAMP signaling, the STAT3 signaling pathway, etc. In addition to
these classical targets, nutraceuticals are also being realized to efficiently modulate emerging targets,
such as cancer stem cells [38–40], microRNAs (miRNAs) [39,41–43], epithelial-mesenchymal transition
(EMT) [44,45] and the causes of epigenetic modifications [46,47].
Through their action against these molecular targets, nutraceuticals attack the cancer cells at many
different levels: they inhibit cancer cells’ proliferation, induce apoptosis/cell cycle arrest and suppress
invasion/metastasis/angiogenesis. These cytotoxic effects are mediated through the action of
nutraceuticals against factors, such as bcl2, survivin, vascular endothelial growth factor (VEGF), matrix
metalloproteinases (MMPs), urokinase-like plasminogen activator (uPA), etc. In addition to numerous
reports on the in vitro effects of nutraceuticals, there are many in vivo reports that document the
beneficial anticancer effects of nutraceuticals in animal model systems; however, control and
Nutrients 2015, 7 325

rationally-designed phase II/III clinical trials are awaited, although some early clinical trials are
beginning to show some promising results.
4. Nutraceuticals as Anticancer Agents: Challenges
With all the available data, it appears that naturally-occurring anticancer agents are well placed to be
employed in the clinical setting for the treatment of human cancers. However, this has not yet happened
in the classical manner of clinical trials (Figure 1). There are few reasons that have obstructed the clinical
development of natural compounds as anticancer agents. The first and foremost reason is the issue of
bioavailability. Study after study has reported that nutraceuticals demonstrate poor bioavailability, when
assessed in pharmacological studies. While this is a major road block, it is important to understand that
these agents are part of the normal human diet, and as part of natural diets, they are absorbed and
processed very efficiently physiologically with sustained low levels, which may be highly important for
rendering their biological activity. This also means that they need to be effective within the short window
ranging from minutes to few hours when they are detectable in circulation. This is not an ideal scenario
according to conventional pharmacology, and thus, such poor bioavailability gets in the way of their
effectiveness as anticancer agents in diseased subjects, as viewed through the lens of classical clinical
trials with pharmacological agents. In order to replicate the in vitro effects, these nutraceuticals should
persist in circulation for longer durations. To partially overcome this bioavailability issue, use of higher
doses has been recommended and evaluated. This has led to the second challenge, the issue of higher
doses-associated unwanted toxicity, even though they are natural agents. As with any drug, even natural
agents can be tolerated up to an extent, and once used at very higher doses, toxic side effects become
more evident.
Does this mean that all of the promising preliminary anticancer activity of nutraceuticals can never
be translated into clinical reality? The answer might not be very straightforward, but efforts are underway
to make sure that such a promise does not go to waste. One strategy to overcome limited bioavailability
is the use of novel formulations that ensure better and sustained systemic release [48–56]. Such
formulations have resulted in better efficacy and need to be tested further in clinical studies. Another
approach is the synthesis of novel analogs of nutraceuticals. A number of analogs of various
nutraceuticals have been reported [40,57–74]. This is another effective strategy to improve the efficacy
of nutraceuticals by chemically modifying the structure of the compound, leading to enhanced
cytotoxicity, as evidenced by lowered IC values. Although it sounds simple, this is a tedious process
50
that involves the synthesis of many putative chemical analogs, keeping intact the main chemical moiety.
Synthesis is then followed by screening of compounds for their anticancer activity. Our own laboratory
has been interested in addressing the bioavailability issue of nutraceutical curcumin through the synthesis
of novel analogs. Our efforts have led to the synthesis of difluorinated curcumin (CDF), which has
demonstrated better efficacy as an anticancer agent with enhanced bioavailability [75–81]. However,
this compound needs further clinical development for the treatment of human malignancies.
Nutrients 2015, 7 326

Figure 1. The importance of nutraceuticals as anticancer agents is increasingly being
recognized. They hold a lot of promise, as evidenced by multiple reports on their ability to
modulate key signaling pathways/molecules that influence tumorigenicity. However, some
challenges, particularly their bioavailability, have hindered their progress through clinical
trials. In order to realize the true potential of nutraceuticals as anticancer agents, the
challenges need to be overcome.
5. NF-κB Signaling: The Master Pathway Regulated by Nutraceuticals
NF-κB (nuclear factor-kappa B) is a crucial signaling pathway involved in the progression of human
cancers [82–85]. NF-κB pathway includes several important molecules, such as NF-κB and IκB Kinase
(IKK); however, NF-κB is the key protein in the pathway that has been extensively implicated as a
promising target for cancer therapy without much success. NF-κB is a transcription factor that exists in
a latent state in the cytoplasm bound to IκB inhibitory proteins. Pro-survival stimuli result in
IKK-dependent phosphorylation and subsequent proteasome-mediated degradation of the inhibitory IκB
proteins. This results in the release of NF-κB, which migrates to the nuclear compartment and regulates
the transcription of multiple target genes. These target genes are largely involved in the regulation of
cell proliferation, invasion and metastasis. Because of such a prominent and central role of NF-κB, its
inhibition by nutraceuticals is considered good proof in support of their anticancer ability. Factors, such
as VEGF, MMPs and uPA, are all influenced by NF-κB signaling, thus providing a direct connection
between NF-κB signaling and an aggressive phenotype, and further provide a proof-of-concept that
naturopathy could be a novel strategy in modern medicine.
The relevance of NF-κB signaling in cancer progression is further confirmed by the fact that this
signaling pathway is probably the most studied pathway when it comes to assessing the activity of
potential anticancer agents. Often, this is the very first pathway evaluated. As a consequence, almost
every single nutraceutical has been documented to inhibit the NF-κB signaling pathway to some extent.
In particular, there is overwhelming data supporting the inhibition of NF-κB signaling by
curcumin [86–89], which almost makes it appear as if curcumin is a specific inhibitor of NF-κB
signaling; however, the benefit of curcumin is limited due, in part, for its poor systemic and target tissue
Nutrients 2015, 7 327

bioavailability. As discussed above, curcumin failed in translational studies because of its poor
bioavailability, and thus, our novel synthetic analog (CDF) is perhaps a successful attempt for improving
the bioavailability of an active natural compound. Our initial experiments revealed that the levels of
CDF were 10-times higher than curcumin in the pancreas of mice [80]. Based on these observations, it
is safe to conclude that the enhanced anti-tumor activity of CDF is in part due to its potent inhibition of
NF-κB signaling and that the activity in the screening assay is also consistent with the pharmacokinetic
results, as discussed above. In addition to curcumin and CDF, a number of other nutraceuticals target
NF-κB, which forms the basis for their anticancer activity [74,90–95].
6. Conclusions and Perspectives
Cancer research has come a long way from the time when searching for single-targeting agents was
the norm in the field of drug discovery. It is now widely accepted that cancer is an even more complicated
disease than ever envisioned, and a tumor mass is composed of a highly heterogeneous population of
cancer cells having aberrations in distinct, yet multiple sets of genes. The tumor cell heterogeneity
together with intrinsic (de novo) and extrinsic (acquired) drug resistance appear to be the key reasons
for the treatment failure of conventional therapeutics. Therefore, a better understanding of drug
resistance phenotype is the current area of research, which has made us realize that the inhibition of the
major signaling pathway often leads to switching of cancer cells to utilize alternate pathways for their
survival and, thus, resist therapeutic benefit. All of this knowledge has led to advocating the use of
combinational therapies or the use of pleiotropic agents, such as naturally occurring anticancer agents of
dietary origin, to achieve better treatment outcomes for patients diagnosed with cancers. To that end,
nutraceuticals have shown great promise in in vitro studies, but have fallen short in translational studies.
The bioavailability of nutraceuticals remains a major concern. One way of overcoming this issue is
through the synthesis of novel analogs of established nutraceuticals. A number of novel nutraceuticals
are under investigation in our laboratory and others throughout the world, and thus, quick and efficient
screening of new and existing compounds will be the key to finding chemical structure(s) that can be
used in the future for the clinical management of human cancers, which clearly support naturopathy as
a tool for modern medicine. In addition to the classical signaling pathways, new screening tools will be
helpful in evaluating emerging molecular targets, such as microRNAs, and target gene expression
modulated by nutraceuticals. This is a step in the right direction that integrates emerging techniques with
state-of-the-art knowledge. Combining this further with computational tools, such as modeling/docking
studies, bioinformatics and systems biology, should be the goal in moving forward the field of
naturopathy in modern medicine.
Author Contributions
All of the authors contributed in the writing and proof-reading of this review article.
Conflicts of Interest
The authors declare no conflict of interest.
Nutrients 2015, 7 328

References
1. Siegel, R.; Ma, J.; Zou, Z.; Jemal, A. Cancer statistics, 2014. CA Cancer J. Clin. 2014, 64, 9–29.
2. Melisi, D.; Piro, G.; Tamburrino, A.; Carbone, C.; Tortora, G. Rationale and clinical use of
multitargeting anticancer agents. Curr. Opin. Pharmacol. 2013, 13, 536–542.
3. Ahmad, A.; Sakr, W.A.; Rahman, K.M.W. Mechanisms and therapeutic implications of cell death
induction by indole compounds. Cancers 2011, 3, 2955–2974.
4. Sarkar, F.H. Nutraceuticals and Cancer; Springer: New York, NY, USA, 2012; Volume 1.
5. Shukla, Y.; George, J. Combinatorial strategies employing nutraceuticals for cancer development.
Ann. N. Y. Acad. Sci. 2011, 1229, 162–175.
6. Russo, G.L. Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem. Pharmacol.
2007, 74, 533–544.
7. Brisdelli, F.; D’Andrea, G.; Bozzi, A. Resveratrol: A natural polyphenol with multiple
chemopreventive properties. Curr. Drug Metab. 2009, 10, 530–546.
8. Deep, G.; Agarwal, R. Antimetastatic efficacy of silibinin: Molecular mechanisms and therapeutic
potential against cancer. Cancer Metastasis Rev. 2010, 29, 447–463.
9. Ahmad, A.; Sakr, W.A.; Rahman, K.M. Novel targets for detection of cancer and their modulation
by chemopreventive natural compounds. Front. Biosci. (Elite Ed.) 2012, 4, 410–425.
10. Soni, D.; Salh, B. A neutraceutical by design: The clinical application of curcumin in colonic
inflammation and cancer. Scientifica (Cairo) 2012, 2012, doi:10.6064/2012/757890.
11. Shehzad, A.; Lee, Y.S. Molecular mechanisms of curcumin action: Signal transduction. Biofactors
2013, 39, 27–36.
12. Gupta, S.C.; Patchva, S.; Aggarwal, B.B. Therapeutic roles of curcumin: Lessons learned from
clinical trials. AAPS J. 2013, 15, 195–218.
13. Borriello, A.; Bencivenga, D.; Caldarelli, I.; Tramontano, A.; Borgia, A.; Zappia, V.; Della Ragione, F.
Resveratrol: From basic studies to bedside. Cancer Treat. Res. 2014, 159, 167–184.
14. Russo, G.L.; Russo, M.; Spagnuolo, C.; Tedesco, I.; Bilotto, S.; Iannitti, R.; Palumbo, R. Quercetin:
A pleiotropic kinase inhibitor against cancer. Cancer Treat. Res. 2014, 159, 185–205.
15. Ahmad, A.; Biersack, B.; Li, Y.; Bao, B.; Kong, D.; Ali, S.; Banerjee, S.; Sarkar, F.H. Perspectives
on the role of isoflavones in prostate cancer. AAPS J. 2013, 15, 991–1000.
16. Genovese, S.; Epifano, F. Auraptene: A natural biologically active compound with multiple targets.
Curr. Drug Targets 2011, 12, 381–386.
17. Rather, M.A.; Bhat, B.A.; Qurishi, M.A. Multicomponent phytotherapeutic approach gaining
momentum: Is the “one drug to fit all” model breaking down? Phytomedicine 2013, 21, 1–14.
18. Gild, M.L.; Bullock, M.; Robinson, B.G.; Clifton-Bligh, R. Multikinase inhibitors: A new option
for the treatment of thyroid cancer. Nat. Rev. Endocrinol. 2011, 7, 617–624.
19. Den Hollander, P.; Savage, M.I.; Brown, P.H. Targeted therapy for breast cancer prevention.
Front. Oncol. 2013, 3, doi:10.3389/fonc.2013.00250.
20. Sabnis, G.; Brodie, A. Adaptive changes results in activation of alternate signaling pathways and
resistance to aromatase inhibitor resistance. Mol. Cell Endocrinol. 2011, 340, 142–147.
21. Jones, A. Combining trastuzumab (herceptin) with hormonal therapy in breast cancer: What can be
expected and why? Ann. Oncol. 2003, 14, 1697–1704.
Nutrients 2015, 7 329

22. Shao, Z.M.; Shen, Z.Z.; Liu, C.H.; Sartippour, M.R.; Go, V.L.; Heber, D.; Nguyen, M. Curcumin
exerts multiple suppressive effects on human breast carcinoma cells. Int. J. Cancer 2002, 98,
234–240.
23. Somers-Edgar, T.J.; Scandlyn, M.J.; Stuart, E.C.; le Nedelec, M.J.; Valentine, S.P.; Rosengren, R.J.
The combination of epigallocatechin gallate and curcumin suppresses ERα-breast cancer cell
growth in vitro and in vivo. Int. J. Cancer 2008, 122, 1966–1971.
24. De Amicis, F.; Giordano, F.; Vivacqua, A.; Pellegrino, M.; Panno, M.L.; Tramontano, D.; Fuqua, S.A.;
Ando, S. Resveratrol, through Nf-Y/p53/Sin3/HDAC1 complex phosphorylation, inhibits estrogen
receptor alpha gene expression via p38MAPK/CK2 signaling in human breast cancer cells. FASEB
J. 2011, 25, 3695–3707.
25. Kang, N.H.; Hwang, K.A.; Lee, H.R.; Choi, D.W.; Choi, K.C. Resveratrol regulates the cell viability
promoted by 17beta-estradiol or bisphenol A via down-regulation of the cross-talk between estrogen
receptor alpha and insulin growth factor-1 receptor in BG-1 ovarian cancer cells. Food Chem. Toxicol.
2013, 59, 373–379.
26. Rajoria, S.; Suriano, R.; George, A.; Shanmugam, A.; Schantz, S.P.; Geliebter, J.; Tiwari, R.K.
Estrogen induced metastatic modulators MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane
in thyroid cancer. PLoS One 2011, 6, doi:10.1371/journal.pone.0015879.
27. Sun, S.H.; Huang, H.C.; Huang, C.; Lin, J.K. Cycle arrest and apoptosis in MDA-MB-231/Her2
cells induced by curcumin. Eur. J. Pharmacol. 2012, 690, 22–30.
28. Catania, A.; Barrajon-Catalan, E.; Nicolosi, S.; Cicirata, F.; Micol, V. Immunoliposome
encapsulation increases cytotoxic activity and selectivity of curcumin and resveratrol against HER2
overexpressing human breast cancer cells. Breast Cancer Res. Treat. 2013, 141, 55–65.
29. McGuire, K.P.; Ngoubilly, N.; Neavyn, M.; Lanza-Jacoby, S. 3,3'-diindolylmethane and paclitaxel
act synergistically to promote apoptosis in HER2/Neu human breast cancer cells. J. Surg. Res. 2006,
132, 208–213.
30. Ahmad, A.; Ali, S.; Ahmed, A.; Ali, A.S.; Raz, A.; Sakr, W.A.; Rahman, K.M.
3,3'-diindolylmethane enhances the effectiveness of herceptin against HER-2/Neu-expressing breast
cancer cells. PLoS One 2013, 8, doi:10.1371/journal.pone.0054657.
31. Sarkar, F.H.; Li, Y. Harnessing the fruits of nature for the development of multi-targeted cancer
therapeutics. Cancer Treat. Rev. 2009, 35, 597–607.
32. Banerjee, S.; Kong, D.; Wang, Z.; Bao, B.; Hillman, G.G.; Sarkar, F.H. Attenuation of
multi-targeted proliferation-linked signaling by 3,3'-diindolylmethane (DIM): From bench to clinic.
Mutat. Res. 2011, 728, 47–66.
33. Li, Y.; Kong, D.; Bao, B.; Ahmad, A.; Sarkar, F.H. Induction of cancer cell death by isoflavone:
The role of multiple signaling pathways. Nutrients 2011, 3, 877–896.
34. Gupta, S.C.; Prasad, S.; Kim, J.H.; Patchva, S.; Webb, L.J.; Priyadarsini, I.K.; Aggarwal, B.B.
Multitargeting by curcumin as revealed by molecular interaction studies. Nat. Prod. Rep. 2011, 28,
1937–1955.
35. Khan, N.; Mukhtar, H. Multitargeted therapy of cancer by green tea polyphenols. Cancer Lett. 2008,
269, 269–280.
Nutrients 2015, 7 330

36. Mukhtar, E.; Adhami, V.M.; Khan, N.; Mukhtar, H. Apoptosis and autophagy induction as
mechanism of cancer prevention by naturally occurring dietary agents. Curr. Drug Targets 2012,
13, 1831–1841.
37. Prakobwong, S.; Gupta, S.C.; Kim, J.H.; Sung, B.; Pinlaor, P.; Hiraku, Y.; Wongkham, S.; Sripa, B.;
Pinlaor, S.; Aggarwal, B.B. Curcumin suppresses proliferation and induces apoptosis in human
biliary cancer cells through modulation of multiple cell signaling pathways. Carcinogenesis 2011,
32, 1372–1380.
38. Kim, S.H.; Sehrawat, A.; Singh, S.V. Dietary chemopreventative benzyl isothiocyanate inhibits
breast cancer stem cells in vitro and in vivo. Cancer Prev. Res. (Phila) 2013, 6, 782–790.
39. Bao, B.; Li, Y.; Ahmad, A.; Azmi, A.S.; Bao, G.; Ali, S.; Banerjee, S.; Kong, D.; Sarkar, F.H.
Targeting CSC-related mirnas for cancer therapy by natural agents. Curr. Drug Targets 2012, 13,
1858–1868.
40. Dandawate, P.; Padhye, S.; Ahmad, A.; Sarkar, F.H. Novel strategies targeting cancer stem cells
through phytochemicals and their analogs. Drug Deliv. Transl. Res. 2013, 3, 165–182.
41. Li, Y.; Kong, D.; Wang, Z.; Sarkar, F.H. Regulation of micrornas by natural agents: An emerging
field in chemoprevention and chemotherapy research. Pharm. Res. 2010, 27, 1027–1041.
42. Saini, S.; Majid, S.; Dahiya, R. Diet, micrornas and prostate cancer. Pharm. Res. 2010, 27,
1014–1026.
43. Chiyomaru, T.; Yamamura, S.; Fukuhara, S.; Yoshino, H.; Kinoshita, T.; Majid, S.; Saini, S.;
Chang, I.; Tanaka, Y.; Enokida, H.; et al. Genistein inhibits prostate cancer cell growth by targeting
miR-34a and oncogenic hotair. PLoS One 2013, 8, doi:10.1371/journal.pone.0070372.
44. Li, W.; Ma, J.; Ma, Q.; Li, B.; Han, L.; Liu, J.; Xu, Q.; Duan, W.; Yu, S.; Wang, F.; et al. Resveratrol
inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the
PI-3k/Akt/NF-κB pathway. Curr. Med. Chem. 2013, 20, 4185–4194.
45. Baribeau, S.; Chaudhry, P.; Parent, S.; Asselin, E. Resveratrol inhibits cisplatin-induced
epithelial-to-mesenchymal transition in ovarian cancer cell lines. PLoS One 2014, 9, doi:10.1371/
journal.pone.0086987.
46. Ahmad, A.; Li, Y.; Bao, B.; Kong, D.; Sarkar, F.H. Epigenetic regulation of mirna-cancer stem cells
nexus by nutraceuticals. Mol. Nutr. Food Res. 2014, 58, 79–86.
47. Hirata, H.; Hinoda, Y.; Shahryari, V.; Deng, G.; Tanaka, Y.; Tabatabai, Z.L.; Dahiya, R. Genistein
downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone
modification in prostate cancer cells. Br. J. Cancer 2014, 110, 1645–1654.
48. Siddiqui, I.A.; Adhami, V.M.; Bharali, D.J.; Hafeez, B.B.; Asim, M.; Khwaja, S.I.; Ahmad, N.;
Cui, H.; Mousa, S.A.; Mukhtar, H. Introducing nanochemoprevention as a novel approach for
cancer control: Proof of principle with green tea polyphenol epigallocatechin-3-gallate. Cancer Res.
2009, 69, 1712–1716.
49. Siddiqui, I.A.; Mukhtar, H. Nanochemoprevention by bioactive food components: A perspective.
Pharm. Res. 2010, 27, 1054–1060.
50. Siddiqui, I.A.; Adhami, V.M.; Ahmad, N.; Mukhtar, H. Nanochemoprevention: Sustained release
of bioactive food components for cancer prevention. Nutr. Cancer 2010, 62, 883–890.